Understanding causal estimates of smoking behaviors for cognitive impairment: A Mendelian randomization study.

Background: Smoking has been linked to dementia, but the causal relationship has not been well established.

Objective: Our study used a Mendelian randomization (MR) framework to examine the impact of different stages and kinds of smoking behavior on cognitive status.

Methods: We analyzed a Health and Retirement Study sample, categorizing cognitive status into three levels (normal, cognitive impairment-no dementia, dementia) and using self-reported smoking behaviors. We used multivariable logistic regressions to examine associations and MR to examine potential causality. We used smoking polygenic scores as instruments for one-sample MR and validated through two-sample MR with genome-wide association study summary statistics.

Results: Current smoking was associated with 1.33 times higher odds of cognitive impairment-no dementia (95% CI: 1.06, 1.65) in European ancestry participants (N = 7708). Among participants who had ever smoked, each 10 additional year of smoking was associated with 1.11 times higher odds of cognitive impairment-no dementia (95% CI: 1.10, 1.22). Using ever smoking polygenic score as a validated instrumental variable, we detected strong causal effects of ever smoking, current smoking, and total smoking years on cognitive impairment (all p < 0.001). Two-sample MR showed no evidence of causality between smoking behaviors and Alzheimer's disease. No causality was observed in the African ancestry sample (N = 1928).

Conclusions: Smoking behavior was cross-sectionally associated with and potentially on the causal pathway of cognitive impairment-no dementia in the larger European ancestry sample. However, no associations were observed with dementia, and the findings did not replicate across ancestry groups. The causal relationship between smoking and cognitive health remains suggestive but not conclusive. Promoting smoking cessation remains a prudent public health strategy to prevent numerous health conditions, and its potential impact on cognitive health warrants further investigation.